Fibroblast Growth Factor (FGF) Receptors (R) R1, R2 and R3 are important regulators of oligodendrocytes (OL) differentiation. Further, R2 is targeted into the myelin membrane, where it may play a role in myelin-axon signaling. The expression of R1, R3 and R2 is carefully regulated during OL differentiation. We hypothesize that the observed multiple responses of OLs to FGF are due to multi-receptor phenomena involving R1, R2 and R3, each of which contributes a subset of the overall phenotype at each stage of the lineage. In AIM I we will examine the role of R2 in an R2-null mouse model we have developed using cre/Iox technology, in which R2 expression is deleted specifically in myelinating cells. We propose that FGF signaling via R2 plays a role in both the regulation of OL terminal differentiation and myelin biogenesis, maintenance and function, including axoglial signaling. Preliminary data indicate that these mice have significant alterations in OL differentiation and myelin-axon interactions. In AIM II we investigate the functional significance of regulated FGF Receptor expression during OL development, applying new tools including FGFs that activate specific FGF receptors, OL cultured from R3- and R2-deficient mice, and SH2 profiling to identify likely down-stream targets of specific FGF receptor activation. In AIM III we note that OL development in vivo is a balanced orchestration of multiple factors produced by multiple cell types. We propose to study the role of FGF in vivo in the context of signaling through all its receptors acting in concert, by either hypostimulating or hyperstimulating the FGF receptors. Against the background of these studies, we then propose to introduce focal demyelination in R2- and R3- null mice in order to study the role of these receptors in remyelination and repair. The long term goal of this project is to understand the functional significance of the rigorously controlled developmental expression of FGF receptors both during OL differentiation leading to myelin biogenesis, as well as in myelin membrane function, maintenance and repair, and to apply this knowledge to an informed intervention in the treatment of demyelinating diseases such as Multiple Sclerosis. [unreadable] [unreadable]